Heart failure with preserved ejection fraction (HFpEF) is a multifactorial and multisystemic disorder that represents more than 50% of all heart failure cases.
Epidemiologic data from the Framingham Study, an international cohort study, shows a rapid increase in the prevalence of HFpEF over the past three decades, from 41% to 56% and, conversely, a decrease in the prevalence of HFrEF from 44% to 31%. 
Because of its complex pathophysiology, increasing prevalence, high mortality and morbidity, and very limited therapeutic options, HFpEF is considered one of the greatest unmet medical needs in cardiovascular medicine.
Patients with HFpEF have higher morbidity, mortality, and rehospitalization. Quality of life in patients with HFpEF is worse than in those with heart failure with reduced ejection fraction (HFrEF).
While HFrEF is dominated by left ventricular (LV) impairment, HFpEF results from a complex interplay of cardiac remodeling, peripheral circulation, and concomitant features including age, hypertension, obesity, and diabetes.
Gaining a better understanding of HFpEF’s complex pathophysiology and its relationship between underlying age-related changes and frequent comorbidities may help us better understand the biology, diagnosis, and treatment of these patients.
What causes HFpEF?
HFpEF affects the left and right ventricles, diastolic and systolic function, atrial reserve, heart rate and rhythm, autonomic control, vasculature and microcirculation, and the periphery.
While dominant contributors can vary from patient to patient, HFpEF is typically displayed as a conglomeration of several reserve impairments that combine to cause symptomatic heart failure (HF).
A great number of studies have attempted to uncover the cellular and molecular basis of HFpEF development, however, its pathophysiology remains complex.
Though the processes leading to the cardiac, vascular, and peripheral limitations that cause HFpEF remain relatively unclear, epidemiological studies have found some leading risk factors for the development of the condition. 
What are the comorbidities and risk factors for HFpEF?
There is a strong association between HFpEF, older age, and comorbidities. HFpEF patients are likely to have a high prevalence of cardiovascular and non-cardiovascular comorbidities, such as obesity, metabolic syndrome, diabetes mellitus type 2, salt-sensitive hypertension, atrial fibrillation (AF), chronic obstructive pulmonary disease, anaemia, and renal dysfunction.[6.7,8]
As life expectancy and comorbidity rates rise, the proportion of HF patients with HFpEF and the impact HFpEF has on healthcare services is projected to increase and become a greater health burden.
The importance of risk factors and comorbidities in HFpEF is recognized in the strong (Class I) recommendation in 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Except for comorbidity-specific guidelines, no HFpEF-specific treatment for comorbidities currently exist at this time.
Here’s what we know so far about some of these risk factors and their involvement in the progression to HFpEF:
Structural and functional changes related to aging are believed to be significant risk factors of HFpEF, for example, ventricular arterial stiffening, vascular dysfunction, impaired Ca2+ regulation, and physical deconditioning. 
HFpEF has traditionally been perceived as a disease of the elderly. The PREVEND study showed that older age was strongly associated with new onset of HFpEF (HR 2.53; 95% CI [1.93–3.30], per 10 years)..
The high comorbidity burden in the elderly is postulated to play a central role in HFpEF’s pathology. Comorbidities have a cumulative and synergistic effect on cardiac function and outcomes.  The elderly with HFpEF have 5.5 noncardiac comorbidities on average. 
Aging promotes coronary microvascular endothelial abnormalities, myocardial remodeling, and dysfunction in HFpEF [13,14,15]. It contributes independently to the deterioration of diastolic function. [16,17].
Recent studies highlight the unique risk factors of younger patients with HFpEF. An analysis by the PREVEND, Framingham Heart Study and the MESA cohort Study explained hypertension, smoking and obesity in the young promote a greater risk for future HFpEF in younger than older individuals. TOPCAT, I-Preserve and CHARM-Preserved showed a higher risk of cardiovascular death, particularly from sudden death in younger patients, despite fewer comorbidities.
Preventative measures early in life in high-risk individuals might prove beneficial to reduce the burden of HFpEF.
Hypertension is the most common co-morbidity in HFpEF patients. Research suggests the prevalence of hypertension ranges between 55% and 90% in HFpEF patients[20,21,22], and that hypertension carries a sixfold increase in HF risk as compared to non-hypertensive individuals.
Hypertension is not only a risk factor for increased LV afterload and pressure-induced hypertrophy, but it is also associated with a chronic proinflammatory state, arterial stiffness, and titin-dependent stiffness, which are central and peripheral mechanisms involved in the progression to HFpEF. 
Chronic arterial hypertension is also a known risk factor for renal impairment, which can lead to a poorer prognosis in HFpEF patients. 
There are multiple ways in which hypertension interacts with other comorbidities, the vasculature, and the heart to predispose to HFpEF, contributing to HFpEF’s complex pathophysiology. 
Despite it being challenging, it’s widely agreed that blood pressure control remains central in the clinical management of hypertensive patients with HFpEF.
Atrial Fibrillation (AF) is a well-known risk factor and prognostic indicator in HFpEF. The prevalence of AF in HFpEF ranges from 15% to 40%,[26,27,28,29] and it seems to implicate a worse prognosis in patients with HFpEF than HFrEF.
If both heart failure and AF coexist, the risk for worse outcomes and hospitalizations increases significantly, with a two-fold increase in mortality.
AF and HFpEF appear to both be manifestations of a common underlying atrial and ventricular myopathy that is triggered when a systemic inflammatory or metabolic disorder causes coronary microvascular dysfunction and fibrosis of the atrial and ventricular myocardium, a process that may be mediated or exacerbated by inflammation in the adjoining epicardial adipose tissue.
The diagnosis of HF can be complicated in the presence of AF because both conditions share common clinical manifestations, such as similar symptoms and elevated B-type natriuretic peptides. Regardless of which disorder presents first, both are or will soon become evident in the same patients.
More than 80% of HFpEF patients are overweight or obese, and obesity is a major risk factor for incidents of HFpEF.
Obesity and its related comorbidities – such as metabolic syndrome, sedentary lifestyle, and hypertension – have been commonly observed alongside HFpEF. They may interact with aging to further increase the risk of developing the condition. 
Obesity is often accompanied by increased epicardial adipose tissue volume, which transduces the effects of these diseases on cardiac function and structure. It has been additionally found to cause systemic inflammation, oxidative stress, and depressed nitric oxide availability that can lead to the manifestation of HFpEF.
A consortium of four large community cohorts (the Cardiovascular Health Study, PREVEND, Framingham Heart Study and MESA) assessing 22,681 individuals showed that every 1 standard deviation increase in BMI was associated with 34% increase in incident HFpEF, consistent with other community studies.[34,35,36]
Diabetes is another major risk factor in patients with HFpEF. At least one-third of patients with HFpEF have a diagnosis of diabetes.
In the CHARM programme, 40% of patients with HFpEF had a diagnosis of diabetes at enrolment and another 22% were prediabetic with hemoglobin A1c between 6.0% and 6.4%.
Like obesity, diabetes is accompanied by increased epicardial adipose tissue volume, which affects cardiac function  and can lead to inflammatory and fibrotic atrial and ventricular myopathy, the two major elements of HFpEF .
In addition to diabetes’ effect on the systemic inflammatory state, the condition can also contribute to the development of HFpEF through other pathways, such as accelerating atherosclerosis, leading to myocardial ischemia. 
Volume overload can also result from the progressive renal dysfunction associated with diabetes. Hyperglycemia and insulin resistance can promote autonomic neuropathy, contributing to cardiac stiffness, hypertrophy, and fibrosis. 
The higher occurrence of HFpEF in women suggests that sex-dependent mechanisms may be involved in HFpEF pathogenesis (Dunlay et al., 2017). In general, women tend to show more concentric LV remodeling, with smaller LV volumes, higher EF, and increased diastolic LV and arterial stiffness. [41, 42].
While gender seems to play a role in HFpEF development and progression, the detailed mechanisms underlying the gender-related differences in HFpEF are not yet understood.
What we do know is that women display a higher left ventricular ejection fraction (LVEF), a worse diastolic function, and fewer co-morbid conditions when compared to men. 
That said, women with HFpEF are more likely to be obese and to have a history of hypertension or renal impairment. More concerning, having hypertension increases the risk of heart failure by 3 times in women, compared to by 2 times in men. [41,42]
The high prevalence of HFpEF in postmenopausal women also hints that menopause-related estrogen dysregulation and the related comorbidities, such as obesity, diabetes, hypertension, and renal dysfunction, may contribute to HFpEF development (Sabbatini and Kararigas, 2020).
Clinical Indicators to Chart the Pathophysiology of HFpEF
Tracking the clinical indicators of HFpEF can help us gain a better understanding of the processes and dysfunctions that might lead to the disorder.
Circulating biomarkers reflect cardiac as well as non-cardiac abnormalities, and their measurements often provide insights into pathophysiological processes associated with HF. The clinical uptake of biomarkers for diagnosing HFpEF has generally been poor, with only cardiac natriuretic peptides (NPs) having emerged as clinically relevant. 
Indicators can include:
- Lower laboratory parameters, including blood urea nitrogen, creatinine, N-terminal pro-B-type natriuretic peptide (NT-proBNP), potassium, uric acid, and ferritin levels, when compared to populations with heart failure with mid-range ejection fraction (HFmrEF).
- Smaller LV end-diastolic and end-systolic dimensions, a lower left atrial volume index and LV mass index, and a higher LVEF when compared to HFmrEF patients.
- Cardiac inflammation
- Significantly higher levels of ST2 and cystatin C than HFmrEF patients.
- Increased collagen content
- Cardiac myocytes that are thicker and shorter than normal
- Reductions in myocardial capillary density
- Concentric organ remodeling with or without hypertrophy.
Holistic schematic of biomarkers in heart failure with preserved ejection fraction (HFpEF) 
New direction needed for HFpEF
There have been great strides taken to understand the epidemiology of HFpEF, but knowledge gaps still exist. Compared with advances in the diagnosis and treatment of HFrEF, HFpEF continues to be a great enigma.
The development of HFpEF involves a complex and multi-system integration of dysfunction, which makes it difficult to succinctly track its causes.
We do know that risk factors such as aging, obesity, and diabetes can play a role in its progression, alongside clinical indicators of HFpEF such as chronic cardiac inflammation. However, there is a lack of precise indicators for diagnosing HFpEF and a high prevalence of comorbidities that may interfere with HFpEF diagnosis.
More research regarding sex/gender, racial/ethnic, geographical, and socioeconomic variations in the prevalence, incidence, and outcomes are needed to address the global burden of HFpEF.
Related read: Ultromics Joins FNIH, one of the largest and most respected organizations for healthcare within the United States, in a $37 million, 5-year initiative to improve HFpEF classification and treatment.
Optimized care pathways and prevention through early diagnosis and treatment of risk factors is currently the best approach to reducing hospitalizations through a seamless inpatient and outpatient care structure.
Pfeffer MA, Shah AM, Borlaug BA. Heart failure with preserved ejection fraction in perspective. Circ Res 2019; 124: 1598–1617.
Vasan RS et al (2018) Epidemiology of left ventricular systolic dysfunction and heart failure in the Framingham study: an echocardiographic study over 3 decades. JACC Cardiovasc Imaging 11(1):1–11
Shah SJ, et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation. 2016;134:73–90.
Iacopo Olivotto Eur Heart J. 2022 Dec 30;ehac764. doi: 10.1093/eurheartj/ehac764. Genetic causes of heart failure with preserved ejection fraction: emerging pharmacological treatments
Chao Ma et al, Heart failure with preserved ejection fraction: an update on pathophysiology, diagnosis, treatment, and prognosis. Braz J Med Biol Res. 2020; 53(7): e9646.
Yancy CW, Lopatin M, Stevenson LW, et al. for the ADHERE Scientific Advisory Committee and Investigators. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function. A Report from the Acute Decompensated Heart Failure National Registry (ADHERE) J Am Coll Cardiol. 2006;47:76–84. doi: 10.1016/j.jacc.2005.09.022.
Fonorow GC, Stough WG, Abraham WT, OPTIMIZE-HF Investigators and Hospitals et al. Characteristics, treatments and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50:768–777. doi: 10.1016/j.jacc.2007.04.064.
Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012;59:998–1005. doi: 10.1016/j.jacc.2011.11.040
Heidenreich et al. 2022 AHA/ACC/HFSA Heart Failure Guideline
Brouwers FP, de Boer RA, van der Harst P et al. Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND. Eur Heart J. 2013;34:1424–31.
Murad K, Kitzman D. Frailty and multiple comorbidities in the elderly patient with heart failure: implications for management. Heart Fail Rev. 2011;17:581–8.
Ather S, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012;59:998–1005
Franssen C, et al. Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart Fail. 2015;4:312–24.
Pedone C, Roshanravan B, Scarlata S, Patel KV, Ferrucci L, Incalzi RA. Longitudinal association between serum leptin concentration and glomerular filtration rate in humans. PLoS ONE. 2015;10:e0117828.
Bouthoorn S, et al. The prevalence of left ventricular diastolic dysfunction and heart failure with preserved ejection fraction in men and women with type 2 diabetes: a systematic review and meta-analysis. Diab Vasc Dis Res. 2018;15:477–93.
Gottdiener JS, McClelland RL, Marshall R et al. Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. Ann Intern Med. 2002;137:631–9. doi: 10.7326/0003-4819-137-8-200210150-00006
Bursi F, Weston SA, Redfield MM et al. Systolic and diastolic heart failure in the community. JAMA. 2006;296:2209–16. doi: 10.1001/jama.296.18.2209.
Tromp J, Paniagua SMA, Lau ES et al. Age dependent associations of risk factors with heart failure: pooled population based cohort study. BMJ. 2021;372:n461. doi: 10.1136/bmj.n461.
 Sotomi Y, Hikoso S, Nakatani D, et al. Sex differences in heart failure with preserved ejection fraction. J Am Heart Assoc 2021;10:e018574.
Bhatia RS, Tu JV, Lee DS et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355:260–9.
Yancy CW, Lopatin M, Stevenson LW et al. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) database. J Am Coll Cardiol. 2006;47:76–84.
Lee DS, Gona P, Vasan RS et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham Heart Study of the National Heart, Lung, and Blood Institute. Circulation. 2009;119:3070–7. doi: 10.1161/CIRCULATIONAHA.108.815944.
Andersson B, Waagstein F. (1993). Spectrum and outcome of congestive heart failure in a hospitalized population. Am Heart J 126: 632-640.
Yan Tu et al. Similarities and Differences Between HFmrEF and HFpEF Front. Cardiovasc. Med., 2021, https://doi.org/10.3389/fcvm.2021.678614
Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62:263–71. doi: 10.1016/j.jacc.2013.02.092
Patel RB, Vaduganathan M, Shah SJ, Butler J. Atrial fibrillation in heart failure with preserved ejection fraction: insights into mechanisms and therapeutics. Pharmacol Ther. 2016 [Epub ahead of print]
Lam CS, Rienstra M, Tay WT, et al. Atrial fibrillation in heart failure with preserved ejection fraction: association with exercise capacity, left ventricular filling pressures, natriuretic peptides, and left atrial volume. JACC Heart Fail. 2017;5:92–98.
Santhanakrishnan R, Wang N, Larson MG, et al. Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in preserved versus reduced ejection fraction. Circulation. 2016;133:484–492.
Zakeri R, Chamberlain AM, Roger VL, Redfield MM. Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction: a community-based study. Circulation. 2013;128:1085–1093
Lam CS, Rienstra M, Tay WT, et al. Atrial fibrillation in heart failure with preserved ejection fraction: association with exercise capacity, left ventricular filling pressures, natriuretic peptides, and left atrial volume. JACC Heart Fail. 2017;5:92–98
Kanako Teramoto et al, Epidemiology and Clinical Features of Heart Failure with Preserved Ejection Fraction, Card Fail Rev. 2022. doi: 10.15420/cfr.2022.06
Yogesh N. V. Reddy, Vojtech Melenovsky et al. High-Output Heart Failure: A 15-Year Experience. J Am Coll Cardiol. 2016 Aug, 68 (5) 473–482
Owan TE, Hodge DO, Herges RM et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251–9
Ho JE, Lyass A, Lee DS et al. Predictors of new-onset heart failure: differences in preserved versus reduced ejection fraction. Circ Heart Fail. 2013;6:279–86. doi: 10.1161/CIRCHEARTFAILURE.112.972828
Savji N, Meijers WC, Bartz TM et al. The association of obesity and cardiometabolic traits with incident HFpEF and HFrEF. JACC Heart Fail. 2018;6:701–9. doi: 10.1016/j.jchf.2018.05.018.37 - Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail 2011;13:18–28.
Kristensen SL, Jhund PS, Lee MMY, et al. Prevalence of prediabetes and undiagnosed diabetes in patients with HFpEF and HFrEF and associated clinical outcomes. Cardiovasc Drugs Ther 2017;31:545–9.
Packer M. Epicardial adipose tissue may mediate deleterious effects of obesity and inflammation on the myocardium. J Am Coll Cardiol. 2018;71:2360–2372. doi: 10.1016/j.jacc.2018.03.509
Packer M. The epicardial adipose inflammatory triad: coronary atherosclerosis, atrial fibrillation, and heart failure with a preserved ejection fraction. Eur J Heart Fail. 2018;20:1567–1569. doi: 10.1002/ejhf.1294.
Dunlay S. M., Roger V. L., Redfield M. M. (2017). Epidemiology of Heart Failure with Preserved Ejection Fraction. Nat. Rev. Cardiol. 14, 591–602. 10.1038/nrcardio.2017.65
- Sabbatini A. R., Kararigas G. (2020). Menopause-Related Estrogen Decrease and the Pathogenesis of HFpEF. J. Am. Coll. Cardiol. 75, 1074–1082. 10.1016/j.jacc.2019.12.049
- Antoni Bayés-Genís et al. Biomarkers in Heart Failure with Preserved Ejection Fraction. Cardiac Failure Review. 2022